The objective of this proposal is to study the chemical, biochemical and pharmacological effects of N-chloroethylnorapomorphine (NCA), a novel and intriguing probe of dopamine receptors. Preliminary studies indicate that this agent may have long lasting, possibly irreversible, interactions with DA receptors in rodent forebrain and in the peripheral vascular receptor in the dog. We seek further evidence that pretreatment of NCA to rodents provides long lasting blockage of dopamine-sensitive adenylate cyclase in striatal homogenates of mouse and rat, and that the interaction is selective in excluding noradrenergic Beta-sensitive adenylatre cyclase responses in cortex slices. The proposed synthesis of 3H-NCA would be crucial in the study of the chemistry and pharmacology of interactions between such a DA receptor probe and tissue binding sites and for taking the first step toward isolating the binding sites themselves. The specific aim of these experiments is to synthesize sufficient quantities of NCA and 3H-NCA and its congeners for additional pharmacological studies, and to synthesize structures which would selectively label DA receptors. We intend to investigate whether the blockade of the dopaminergic receptor by NCA is mediated through the aziridinium species and to study the rate of formation of the aziridinium cation under physiological conditions by high resolution nuclear magnetic resonance techniques. We will use the NCA-DA receptor interaction as a means of characterizing the kinetics and chemistry of DA agonist and antagonist action on the receptor. The continued in vitro and in vivo evaluation of NCA on dopaminergic systems will bve carried out in collaboration with several laboratories. It is expected that these studies will be of fundamental interest in the evaluation of the chemical and pharmacological interactions between such a dopamine receptor antagonist as NCA and dopamine agonist and antagonist tissue binding sites.